Pulmonary Arterial Hypertension Medications Research Articles

Abstract 328: An Outcomes Assessment of Vasodilator Therapy in Pulmonary Arterial Hypertension through Meta-analysis of 31 Randomized Controlled Trials

Rationale: Pulmonary Arterial Hypertension (PAH), a rapidly progressive disease w/high mortality, has an annual therapy cost up to $100,000/yr. We sought to review the RCTs conducted to evaluate the effect of pulmonary vasodilators (PVDs) on outcomes in PAH. Methods: We conducted a systematic review and meta-analysis using MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus (inceptions-January 2014) of RCTs in PAH. Data on all-cause mortality and changes in mean pulmonary artery pressure (mPAP), cardiac output (CO), and pulmonary vascular resistance (PVR) were abstracted when available. Summary relative risks (RR) and 95% confidence intervals (CI) for each outcome were calculated using a random effects model comparing various PVDs with placebo/control. Results: The analysis included 31 RCTs (6,271 patients, 77% female, 70% Caucasian, mean age 47±6yr). Median f/u was 12 weeks (18 trials had f/u of ≤12 weeks, and only 5 followed patients ≥6mos). Although no trial evaluated mortality as the primary endpoint, mortality was reported in 27 of the 31 trials. When analyzed overall PVDs demonstrated a mortality benefit with RR = 0.77 (95% CI = 0.60 - 0.98, I 2 = 0%), however prostacyclins were the only class of agents which independently demonstrated a significant mortality benefit, RR = 0.62 (95% CI 0.39-0.99, I 2 = 0%). Oral PVDs demonstrated no benefit on PAH mortality, RR = 0.85 (95% CI 0.65-1.12, I 2 = 0.0%). Many studies reported ≤1 death in at least one treatment arm, which produced unstable RR estimates and wide CIs. As a result, the mortality benefit and lack of heterogeneity observed in pooled estimates may be driven by these RCTs. When we limited the analysis to only studies with at least 2 deaths in both treatment arms (N=9), the mortality benefit for PVDs was no longer significant (RR 0.86, CI 0.66-1.12, I 2 =0%). Mean change in mPAP with all PVDs was -3.5 mmHg, (95% CI -4.2 - -2.8), compared to placebo 0.6 mmHg (95% CI 0.1 - 1.1), p<0.001. Mean increase in CO with PVDs was 0.6 L/min (95% CI 0.4 - 0.9 L/min) compared to placebo of -0.02 L/min (95% CI -0.15 - 0.1 L/min), p<0.001. PVR decreased by 212 dynes/s/cm 5 (95% CI 178 - 244) in PVD arms and increased by 43 dynes/s/cm 5 (95% CI 12 - 74) in placebo arms, p<0.001. No surrogate marker was predictive of changes in mortality. Patient reported outcomes were reported in 80% of RCTs but there was inconsistency in the measurements reported. Conclusion: The RCT literature on PAH medications focuses on short-term studies and surrogate endpoints. None was designed for mortality or patient-reported outcome measures. Only prostacyclins showed a mortality benefit in PAH, however, the mortality benefit for prostacyclins is based on secondary endpoints in small studies. There remains substantial uncertainty about the benefits of these expensive medications based on the existing trial evidence.

Ambrisentan: a guide to its use in pulmonary arterial hypertension in the EU

Ambrisentan [Volibris® (EU), Letairis® (USA)] is an effective and well-tolerated first-line option for the treatment of adults with pulmonary arterial hypertension (PAH) classified as WHO functional class II or III. Ambrisentan provides sustained improvements in exercise capacity and dyspnoea, stabilizes WHO functional class, increases time to clinical worsening, and has an acceptable tolerability and safety profile. Ambrisentan is associated with fewer drug interactions than other available endothelin-1 receptor antagonists, may be used concomitantly with other common PAH medications, is associated with a low risk of liver function abnormalities, and has a convenient once-daily oral administration regimen.

Transition from intravenous or subcutaneous prostacyclin therapy to inhaled treprostinil in patients with pulmonary arterial hypertension: a retrospective case series.

Inhaled treprostinil represents an attractive alternative to the other available prostacyclin formulations by obviating the use of continuous infusions and its associated risks. Published evidence describing the process of transition from infusion prostacyclin therapy to inhaled treprostinil is limited. The purpose of this report is to describe an inpatient protocol for transitioning patients with pulmonary arterial hypertension (PAH) from intravenous (IV) or subcutaneous (SQ) prostacyclin therapy to inhaled treprostinil. A retrospective case cohort study was performed evaluating medical records of three patients undergoing transition from IV/SQ continuous infusion prostacyclin therapy to inhaled treprostinil. The transition protocol and clinical data were collected prospectively. Haemodynamics, six-min walk distance (6MWD), World Health Organization (WHO) functional class, modified Borg Dyspnea Score and brain natriuretic peptide prior to and after transition remained similar. All patients were receiving concomitant oral PAH medications prior to and after conversion. Adverse effects during the change were mild. No patients discontinued inhaled treprostinil following transition. At long-term follow-up, functional class remained stable at WHO functional class II or better. Patient 1 and Patient 3 demonstrated stable to modest improvement in 6MWD, whereas Patient 2 had a slight decrease in 6MWD. The transition to inhaled treprostinil from IV/SQ infusion prostacyclin therapy appears to be safe in carefully selected patients. Our report describes a standard method used to transition patients from IV/SQ infusion prostacyclin to inhaled treprostinil.

Challenges in Endpoint Development for Pulmonary Hypertension Trials in Children

There are currently 12 medications approved for use in the treatment of pulmonary arterial hypertension (PAH) in adults. These include endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclins. However, in children there are no approved targeted PAH medications, with the exception of inhaled nitric oxide for treatment of hypoxemic respiratory failure in neonates. This review will address some of the challenges in the development of treatments for children, including lessons from recent trials, endpoints for clinical trials, and challenges with drug approval in children.

Assessment and Prognostic Relevance of Right Ventricular Contractile Reserve in Patients With Severe Pulmonary Hypertension

This study sought to analyze a new approach to assess exercise-induced pulmonary artery systolic pressure (PASP) increase by means of stress Doppler echocardiography as a possible measure of right ventricular contractile reserve in patients with severe pulmonary hypertension and right heart failure. In this prospective study, patients with invasively diagnosed pulmonary arterial hypertension or inoperable chronic thromboembolic pulmonary hypertension and impaired right ventricular pump function despite a stable targeted pulmonary arterial hypertension medication underwent a broad panel of noninvasive assessments, including stress echocardiography and cardiopulmonary exercise testing. On the basis of the assumption that exercise-induced PASP is a measure of right ventricular contractile reserve, patients were classified into 2 groups according to an exercise-induced PASP increase above or below the median. Patients were followed up for 3.0 ± 1.8 years. Univariate and multivariate analyses were used for factors predicting survival. Of 124 patients, 66 were below the median exercise-induced PASP increase of 30 mm Hg (low PASP), and 58 patients were above the median (high PASP). These groups were not significantly different in terms of medication and resting hemodynamics. Low PASP was associated with a significantly lower 6-minute walking distance, peak o2 per kilogram, and 1-, 3-, and 4-year survival rates (92%, 69%, and 48%, respectively, versus 96%, 92%, and 89%). In the multivariate Cox model analysis adjusted for age and sex, PASP increase during exercise and peak o2 per kilogram remained independent prognostic markers (hazard ratio, 2.56 for peak o2 per kilogram and 2.84 for PASP increase). Exercise-induced PASP increase is of high clinical and prognostic relevance in pulmonary hypertension patients and may indicate right ventricular contractile reserve. Stress Doppler echocardiography may be a useful tool for prognostic assessment in pulmonary hypertension patients.

Magnetic Resonance Imaging of the Right Ventricle in Pediatric Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) causes changes in the right ventricle (RV), affecting RV size and function, ultimately leading to death. These changes have been evaluated by cardiac MRI (CMR) in adults with PAH, but not in children. Using CMR in pediatric patients with PAH, we examined how RV size and function (1) compare to normal data, (2) change over time, and (3) compare to similar studies in the adult population. Data from two institutions were retrospectively reviewed. Subjects with PAH and a CMR were included. Baseline CMR variables (right and left ventricular end-diastolic and end-systolic volumes indexed for body surface area, and calculated stroke volume and ejection fraction) were compared to normative data and follow-up CMR data. Twenty-six subjects (15 female), age 2-16 (mean 11) years, with idiopathic PAH were included. All patients were on PAH medication, and 65% on prostacyclin therapy. The baseline 6-Minute Walk Distance (6MWD; 481 ± 137) was normal. RV volumes and ejection fraction were markedly abnormal compared to normal data (P < 0.001). Follow-up CMRs were analyzed in 15 patients. RV volumes and function and LV stroke volume showed no significant change over one year. Our pediatric patients with PAH have markedly abnormal right ventricles by CMR but have normal walk distances. The lack of change in CMR parameters over one year may represent a stable cohort and is different than similar studies in adults.

Modern Age Pathology of Pulmonary Arterial Hypertension

The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Assessment of pulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH.

Treatment patterns and healthcare system burden of managed care patients with suspected pulmonary arterial hypertension in the United States

Objectives:To describe treatment patterns and healthcare burden among individuals with suspected pulmonary arterial hypertension (PAH), as identified through a practice guideline-based healthcare claims algorithm.Methods:Adults with evidence of PAH from 1 January 2004 (commercial and Medicaid) or 1 July 2006 (Medicare Advantage) through 30 June 2008 were identified. Given the lack of an ICD-9 code for PAH, an algorithm was developed requiring: (1) ≥1 claim for PAH medication (index date); (2) ≥1 claim with a pulmonary hypertension diagnosis code in the 6-month pre-index period (baseline) or within 90 days post-index; (3) a right heart catheterization or pulmonary hypertension-related inpatient stay during baseline or within 90 days post-index; and (4) continuous health plan enrollment for 6 months pre-index and ≥6 months post-index. Patients with PAH-specific medications during baseline were excluded. Treatment patterns, healthcare utilization, and costs were assessed during the period ending with the earlier of health plan disenrollment or 31 December 2008.Results:Among the 521 included patients, 69% were female. Most patients (94%) initiated treatment with monotherapy (most commonly sildenafil or bosentan), and 12.7% of all patients augmented their therapy by the end of the observation period. The medication possession ratio was 0.96 each for ambrisentan (SD = 0.04), bosentan (SD = 0.04), and sildenafil (SD = 0.05). Overall, 72.6% of patients discontinued therapy with a mean of 149 (SD = 170) days until discontinuation. A mean (SD) of 2.14 (1.82) all-cause office and 1.64 (1.98) outpatient visits occurred per patient per month. Mean PAH-related healthcare costs were $6617 per patient per month, comprising 71% of all-cause costs. The guideline-based algorithm may not have perfectly captured patients with PAH.Conclusions:Patients with suspected PAH were likely to initiate treatment with oral monotherapy, had high compliance rates, and received close ambulatory follow-up. PAH-related costs constituted the majority of all-cause healthcare costs.

Clinical Worsening During Long-Term Follow-Up in Inoperable Chronic Thromboembolic Pulmonary Hypertension

Pulmonary endarterectomy is the treatment of choice in chronic thromboembolic pulmonary hypertension (CTEPH). Modern pulmonary vasoactive medication (like endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins) is used in patients with an inoperable disease and improved prognosis. We evaluate mortality and time to clinical worsening (TtCW) in inoperable CTEPH patients during long-term follow-up. All 32 patients with inoperable CTEPH were enrolled between June 2002 and January 2009. TtCW was defined as the combination of death, need for intravenous pulmonary arterial hypertension medication, or 15% decrease in 6-minute walk distance (6-MWD) without improvement in functional class. The Cox proportional hazard regression was used to identify predictors. During a mean follow-up of 3.4 years (range = 0.2-10.2 years), 11 patients died (34%). The 1- and 3-year survival rates were 87 and 77%, respectively. Baseline functional class, 6-MWD, mean pulmonary artery pressure, and pulmonary vascular resistance were predictors for survival. Clinical worsening occurred in 16 patients (50%). The 1- and 3-year rates of freedom from clinical worsening were 74 and 60%, respectively. The only predictor for clinical worsening was the baseline 6-MWD. Despite the improvement in medical treatment of inoperable CTEPH, the mortality rate is still high, and clinical worsening occurred in a substantial number of patients during a follow-up of more than 3 years.

Affect of Warfarin on Pulmonary Arterial Hypertension (PAH) Mortality: Facts Have Changed?

PAH is a progressive disease with high mortality. Vascular changes in PAH like vasoconstriction, smooth muscle cell and endothelial proliferation, prothrombotic agents and cytokines are most likely explanation of thrombosis. Guidelines suggest keeping INR between 1.5-2.5 after the diagnosis of PAH. Data from earlier observational studies is mixed and did not take in account known prognostic factors of mortality in PAH like cardiac index (CI), right atrial pressure (RAP), pulmonary arterial pressure (PAP) and wide variety of newer medications for PAH.

Third Party Financial Approval for PAH Medications

The Ask the Expert column highlights challenges faced in caring for patients with pulmonary arterial hypertension (PAH). Commentary in this issue focuses on obtaining financial approvals for therapies; Lori Shope, RN, discusses the PAH medication approval process.

Facilitating Pulmonary Arterial Hypertension Medication Adherence: Patient-centered Management

Facilitating Pulmonary Arterial Hypertension Medication Adherence: Patient-centered Management

Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart

Right heart function is the main determinant of prognosis in pulmonary arterial hypertension (PAH). At present, no treatments are currently available that directly target the right ventricle, as we will demonstrate in this article. Meta-analysis of clinical trials in PAH revealed that current PAH medication seems to have limited cardiac-specific effects when analysed by the pump-function graph. Driven by the hypothesis that "left" and right heart failure might share important underlying pathophysiological mechanisms, we evaluated the clinical potential of left heart failure (LHF) therapies for PAH, based on currently available literature. As in LHF, the sympathetic nervous system and the renin-angiotension-aldosterone system are highly activated in PAH. From LHF we know that intervening in this process, e.g. by angiotensin-converting enzyme inhibition or β-blockade, is beneficial in the long run. Therefore, these medications could be also beneficial in PAH. Furthermore, the incidence of sudden cardiac death in PAH could be reduced by implantable cardioverter-defibrillators. Finally, pilot studies have demonstrated that interventricular dyssynchrony, present at end-stage PAH, responded favourably to cardiac resynchronisation therapy as well. In conclusion, therapies for LHF might be relevant for PAH. However, before they can be implemented in PAH management, safety and efficacy should be evaluated first in well-designed clinical trials.

Cost-Utility of Treatments for Pulmonary Arterial Hypertension

Clinicians must choose between an increasing number of medications for the treatment of pulmonary arterial hypertension (PAH) with different routes of administration, adverse effects, costs and efficacies. We constructed a decision analysis to help inform treatment choices in PAH. We created a Markov-type model to evaluate 1-year treatment with bosentan, treprostinil, epoprostenol, inhaled iloprost, sildenafil, sitaxentan and ambrisentan. Transition probabilities were based on observed transitions between WHO functional classes, adjusted by relative risk of improvement in a 6-minute walk test. Utilities were based on reported values for each functional class, adjusted for burden of treatment administration. Costs were estimated from Medicare and Medicaid reimbursement data. Sensitivity analyses evaluated changes in efficacy, utilities and costs. Treatment with sildenafil was less costly and resulted in a greater gain in quality-adjusted life-years (QALYs) compared with other treatments. Treatment with ambrisentan and bosentan resulted in the same gain in QALYs as sildenafil, but at a higher cost. Sensitivity analyses had minimal impact on these results. Based on this model, sildenafil is a cost-effective treatment for PAH with a low price and a net increase in QALYs. The results from this analysis are a tool to help guide clinicians in deciding which PAH medications to use; however, the final decisions should be individualized because the effectiveness of therapy, resulting utilities and acceptable costs will differ with each patient.

Thrombembolien und pulmonale Hypertonie

Chronic thrombembolic pulmonary hypertension (CTEPH) represents a common type of pulmonary hypertension and is associated with significant morbidity and mortality. The prognosis of this condition reflects the degree of associated right ventricular dysfunction. Unresolved thrombemboli and possible in situ thrombosis lead to obstruction of pulmonary arteries resulting in elevated pressures in those areas of the vasculature that were spared from thromboembolic occlusion. This can resemble pathomechanisms in patients with pulmonary arterial hypertension. However the understanding of pulmonary vascular remodeling in patients with CTEPH is incomplete. Pulmonary endarterectomy of the obstructing thromboembolic material should be performed in patients who are accessible to surgery. In patients who are judged inoperable or with persistent pulmonary hypertension treatment with pulmonary arterial hypertension medications can be considered. This could contribute to improved clinical outcome and survival, whereas further controlled studies are required addressing this question.

HIV-associated pulmonary arterial hypertension: a clinical problem that is here to stay?

HIV-associated pulmonary arterial hypertension (PAH) is a serious complication of HIV infection and associated with high patient mortality. There are multiple similarities between HIV-associated PAH and idiopathic PAH and standard PAH medications have been used to treat the condition with reported success. Prior to the advent of highly active antiretroviral treatments (HAART), the prevalence of the condition in the HIV-infected population was estimated at 0.5%. In a recently published, large, prospective, multi-centre study performed in the HIV-population across France, the prevalence of HIV-associated PAH was estimated at 0.46%. In this article, we provide an overview of HIV-associated PAH and summarise the methodology, pertinent findings and implications of this important paper.

Hemodynamics and Epoprostenol Use Are Associated With Thrombocytopenia in Pulmonary Arterial Hypertension

Thrombocytopenia develops in some patients with advanced pulmonary arterial hypertension (PAH) while receiving IV epoprostenol therapy. In this study, we evaluate whether epoprostenol use, other PAH medication use, hemodynamics, or PAH etiology are associated with thrombocytopenia in PAH. Platelet counts were evaluated in 47 PAH patients receiving IV epoprostenol, and in 44 patients with an inadequate response to initial therapy with oral agents in a cross-sectional study. Associations between thrombocytopenia (platelet count < 150,000/mL) and epoprostenol use, hemodynamics, PAH etiology, and use of other PAH medications were evaluated in univariable and multivariable analyses. PAH subtypes included idiopathic (69%), fenfluramine (18%), connective tissue disease (10%), and congenital heart disease (2%)-associated PAH. Thrombocytopenia was observed in 34% of patients treated with epoprostenol, compared with 15% of patients receiving oral therapy (odds ratio [OR], 2.9; p < 0.05), and the association between epoprostenol and thrombocytopenia remained significant after adjustment for differences in hemodynamics (OR, 5.0; p < 0.05). Right atrial pressure (OR, 1.12 per mm Hg; p < 0.05) and mixed venous oxygen saturation (Svo(2)) [OR, 0.92 per percentage; p < 0.05] were also associated with thrombocytopenia in univariable analyses; after logistic regression analysis, both the use of epoprostenol and Svo(2) were independently associated with thrombocytopenia. In a separate analysis including only patients with current or prior epoprostenol use, epoprostenol dose and right atrial pressure were inversely associated with platelet count. Epoprostenol use and severity of hemodynamic abnormalities are associated with thrombocytopenia in PAH, and these effects appear to be independent and additive.

Present and Prospective Pharmacotherapies in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease leading to obstruction of the small pulmonary arteries. Currently, there are eight approved medications for PAH. This review article focuses on the mechanisms, clinical trials, efficacy, and safety profiles of each of the PAH medications. In addition, this review addresses combination PAH therapy, patient preference, and future therapies.

Medical Therapies for Chronic Thromboembolic Pulmonary Hypertension: An Evolving Treatment Paradigm

Pulmonary endarterectomy (PEA) is recommended as the treatment of choice for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, only a proportion of patients fulfill the criteria for surgical intervention. In addition, operated patients with CTEPH may experience a gradual hemodynamic and symptomatic decline related to a secondary hypertensive arteriopathy in the small precapillary pulmonary vessels. It has also been questioned what can be done to reduce risks from PEA surgery to improve outcome in "high risk" patients with CTEPH with substantial impairment of pulmonary hemodynamics before surgery. Such patients may benefit from preoperative reduction of pulmonary vascular resistance by means of medical therapy. Conventional medical treatments, such as anticoagulation, diuretics, digitalis, and chronic oxygen therapy, show low efficacy in the treatment of CTEPH as they do not affect underlying disease processes. Over the last decade, several novel therapies have been developed for pulmonary arterial hypertension (PAH), including prostacyclin analogs (epoprostenol, beraprost, iloprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase-5 inhibitors (sildenafil). Evidence of efficacy in PAH, coupled with studies showing histopathologic similarities between CTEPH and PAH, provides a rationale to extend the use of some of these medications to the treatment of CTEPH. However, direct evidence from clinical trials in CTEPH is limited to date. This article reviews evidence supporting, and issues surrounding, the possible use of novel PAH medications in CTEPH.

Pulmonary Arterial Hypertension

I am very happy to offer this issue of Seminars in Respiratory and Critical Care Medicine, which addresses important clinical and translational topics from leaders in the field of pulmonary arterial hypertension (PAH). I greatly appreciate the insight of Dr. Joseph Lynch, the editor in chief for Seminars, regarding the importance of this topic and for allowing me to be involved. The expert contributors have provided thoughtful, detailed, state-of-the-art reviews on their respective topics. Although 15 years ago there were no Food and Drug Administration (FDA)-approved medications for PAH, basic and clinical research in this area has increased exponentially and now oral, inhaled, and parenteral medications have been tested, proven, and approved. Understanding of genetic, pathogenetic, epidemiological, clinical, and therapeutic aspects of the disease have increased dramatically. These substantial advances have been welcomed by patients and clinicians alike.